Autism is characterized as a qualitative impairment in reciprocal social interaction and communication, with a restricted, repetitive and stereotyped pattern of behavior, interest, and activities. Autism is the most common condition in a group of developmental disorders of the brain known as the autism spectrum disorders (ASDs), including autistic disorder, Asperger syndrome, and pervasive developmental disorder not otherwise specified. Autism affects as many as six in a thousand children and adults. Although innumerable landmark advances have been achieved in the medical sciences, our knowledge about pathophysiology of autism is still very limited. Von Economo neurons (VENs) are large, bipolar, spindle shaped neurons that are most abundant in the human anterior cingulate cortex (ACC) and fronto-insular cortex (FI) and may be involved in the fast and intuitive assessment of complex situations. Deficiencies of VENs in these regions may result in the inability to process complex, unpredictable, and novel information in a social context. There is evidence linking the behavioral deficits observed in patients with autism to the functions of these brain regions, suggesting that the impairments of social and cognitive abilities may relate to abnormal development of VENs. We propose to investigate abnormalities of ACC- and FI-related brain networks involved in both low-level sensory and perceptual and high-level cognitive processes in high-functioning patients with ASD. We hypothesize that, compared to normal controls, there will be a core deficit in the ACC and FI in patients with ASD in terms of abnormal functional activation and connectivity. We will utilize a modified anticipatory stimulation paradigm as well as an empathy and judging other's pain task, and employ multi-modal magnetic resonance imaging (MRI) methods including event related functional MRI, morphometric MRI, and diffusion tensor imaging to test the hypotheses. We will also explore the association between patients'imaging data and the severity of deficits in the three symptom domains of autism. This innovative approach involving the integration of sensory/perceptual and cognitive tasks, multi-modal neuroimaging, and clinical testing, as well as linking of this project to other ongoing studies that directly investigate VENs at the neuronal level, will provide specific and comprehensive functional and anatomical insight into the neural mechanisms of this disorder, which will enlighten our understanding of autism at both neuronal and cognitive levels and may also guide novel treatment approaches. PUBLIC HEALTH RELEVANCE: Autism is characterized as a qualitative impairment in reciprocal social interaction and communication, with a restricted, repetitive and stereotyped pattern of behavior, interest, and activities, affecting as many as six in a thousand children and adults. Although innumerable landmark advances have been achieved in the medical sciences, our knowledge about pathophysiology of autism is still very limited. This innovative approach involving the integration of sensory/perceptual and cognitive tasks, multi-modal neuroimaging, and clinical testing will provide specific and comprehensive functional and anatomical insight into the neural mechanisms of this disorder and may also guide novel treatment approaches.